Outcome of neoadjuvant chemotherapy in BRCA1/2 mutation positive women with advanced-stage Müllerian cancer


      • Patients with germline BRCA mutations had improved outcomes with NAC compared to patients with unknown BRCA status.
      • The outcomes of NAC in BRCA mutation positive patients were more favorable than the outcomes reported in the literature.
      • This is the first study evaluating the outcome of NAC in BRCA mutation positive patients with advanced-stage Mullerian cancer.



      To investigate whether patients with germline BRCA1/2 mutations who received neoadjuvant chemotherapy (NAC) for advanced-stage Müllerian cancer (MC) have an improved outcome compared to patients who did not undergo genetic testing.


      Three hundred and two patients who received NAC for stage III–IV MC were identified from a multi-institutional study involving Cleveland Clinic and Brigham and Women's Hospital for 2000–2014 and 2010–2014 respectively. Patients were divided into 3 cohorts: patients with germline BRCA1/2 mutations (BRCA_mut+; N = 30), patients with no genetic testing (BRCA_mut_unk; N = 166) and patients with negative genetic testing (BRCA_mut−, N = 106).


      There were no differences in the clinical characteristics and rates of complete cytoreduction and bowel resection between the three groups. BRCA_mut+ had longer PFS compared to BRCA_mut_unk and BRCA_mut− (19.1 vs. 15.1 vs. 15.7 months respectively. However, this difference was not statistically significant (p = 0.48). Patients with BRCA2 mutation had non-significant trend toward longer PFS compared to patients with unknown BRCA or BRCA1 mutation (20.2 vs. 15.1 vs. 14.8 months respectively, p = 0.58). BRCA_mut+ and BRCA_mut− had longer overall survivals (OS) compared to BRCA_mut_unk patients (50.5 vs. 54.1 vs. 36.5 months respectively, p = 0.009). In multivariable analyses, controlling for age, stage and complete cytoreduction, BRCA_mut_unk was associated with worse PFS (HR 1.44, 95% CI 1.01–2.05, p = 0.045) and OS (HR 2.67, 95% CI 1.33–5.36, p = 0.006).


      Patients with germline BRCA mutations had improved outcomes with NAC compared to patients with unknown BRCA status. These outcomes were more favorable compared to the outcome of NAC in prior studies.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Gynecologic Oncology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Siegel R.L.
        • Miller K.D.
        • Jemal A.
        Cancer statistics.
        CA Cancer J Clin. 2015; 65: 5-29
        • Bookman M.A.
        • Brady M.F.
        • McGuire W.P.
        • Harper P.G.
        • Alberts D.S.
        • Friedlander M.
        • Colombo N.
        • Fowler J.M.
        • Argenta P.A.
        • De Geest K.
        • Mutch D.G.
        • Burger R.A.
        • Swart A.M.
        • Trimble E.L.
        • Accario-Winslow C.
        • Roth L.M.
        Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a phase III trial of the Gynecologic Cancer Intergroup.
        J Clin Oncol. 2009; 27: 1419-1425
        • Armstrong D.K.
        • Bundy B.
        • Wenzel L.
        • Huang H.Q.
        • Baergen R.
        • Lele S.
        • Copeland L.J.
        • Walker J.L.
        • Burger R.A.
        Intraperitoneal cisplatin and paclitaxel in ovarian cancer.
        N Engl J Med. 2006; 354: 34-43
        • Katsumata N.
        • Yasuda M.
        • Takahashi F.
        • Isonishi S.
        • Jobo T.
        • Aoki D.
        • Tsuda H.
        • Sugiyama T.
        • Kodama S.
        • Kimura E.
        • Ochiai K.
        • Noda K.
        Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial.
        Lancet. 2009; 374: 1331-1338
      1. Vergote I, Trope CG, Amant F, Kristensen GB, Ehlen T, Johnson N, Verheijen RH, van der Burg ME, Lacave AJ, Panici PB, Kenter GG, Casado A, Mendiola C, Coens C, Verleye L, Stuart GC, Pecorelli S, Reed NS. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 363: 943–53.

        • Kehoe S.M.K.
        • Shibata T.
        • Sato A.
        • Fakuda H.
        • Thulkar H.
        • Deo S.
        Upfront surgery versus neoadjuvant chemotherapy for newly diagnosed advanced ovarian cancer: results from the MRC CHORUS trial.
        ASCO meeting abstracts. 2013; 31: 5500
      2. Alsop K, Fereday S, Meldrum C, deFazio A, Emmanuel C, George J, Dobrovic A, Birrer MJ, Webb PM, Stewart C, Friedlander M, Fox S, Bowtell D, Mitchell G. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol 30: 2654–63.

      3. Walsh T, Casadei S, Lee MK, Pennil CC, Nord AS, Thornton AM, Roeb W, Agnew KJ, Stray SM, Wickramanayake A, Norquist B, Pennington KP, Garcia RL, King MC, Swisher EM. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A 108: 18032–7.

      4. Yang D, Khan S, Sun Y, Hess K, Shmulevich I, Sood AK, Zhang W. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA 306: 1557–65.

      5. Hyman DM, Zhou Q, Iasonos A, Grisham RN, Arnold AG, Phillips MF, Bhatia J, Levine DA, Aghajanian C, Offit K, Barakat RR, Spriggs DR, Kauff ND. Improved survival for BRCA2-associated serous ovarian cancer compared with both BRCA-negative and BRCA1-associated serous ovarian cancer. Cancer 118: 3703–9.

      6. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®); Genetic/Familial High-Risk Assessment: Breast and Ovarian; Version 1.
        (Accessed on May 29th, 2015)
      7. Glasgow MA, Yu H, Rutherford TJ, Azodi M, Silasi DA, Santin AD, Schwartz PE. Neoadjuvant chemotherapy (NACT) is an effective way of managing elderly women with advanced stage ovarian cancer (FIGO Stage IIIC and IV). J Surg Oncol 107: 195–200.

        • Griffiths C.T.
        Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma.
        Natl Cancer Inst Monogr. 1975; 42: 101-104
        • Bristow R.E.
        • Tomacruz R.S.
        • Armstrong D.K.
        • Trimble E.L.
        • Montz F.J.
        Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis.
        J Clin Oncol. 2002; 20: 1248-1259
        • Chi D.S.
        • Liao J.B.
        • Leon L.F.
        • Venkatraman E.S.
        • Hensley M.L.
        • Bhaskaran D.
        • Hoskins W.J.
        Identification of prognostic factors in advanced epithelial ovarian carcinoma.
        Gynecol Oncol. 2001; 82: 532-537
        • Le T.
        • Krepart G.V.
        • Lotocki R.J.
        • Heywood M.S.
        Does debulking surgery improve survival in biologically aggressive ovarian carcinoma?.
        Gynecol Oncol. 1997; 67: 208-214
        • Chi D.S.
        • Eisenhauer E.L.
        • Lang J.
        • Huh J.
        • Haddad L.
        • Abu-Rustum N.R.
        • Sonoda Y.
        • Levine D.A.
        • Hensley M.
        • Barakat R.R.
        What is the optimal goal of primary cytoreductive surgery for bulky stage IIIC epithelial ovarian carcinoma (EOC)?.
        Gynecol Oncol. 2006; 103: 559-564
        • Winter III, W.E.
        • Maxwell G.L.
        • Tian C.
        • Carlson J.W.
        • Ozols R.F.
        • Rose P.G.
        • Markman M.
        • Armstrong D.K.
        • Muggia F.
        • McGuire W.P.
        Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study.
        J Clin Oncol. 2007; 25: 3621-3627
        • Hyman D.M.
        • Long K.C.
        • Tanner E.J.
        • Grisham R.N.
        • Arnold A.G.
        • Bhatia J.
        • Phillips M.F.
        • Spriggs D.R.
        • Soslow R.A.
        • Kauff N.D.
        • Levine D.A.
        Outcomes of primary surgical cytoreduction in patients with BRCA-associated high-grade serous ovarian carcinoma.
        Gynecol Oncol. 2012; 126: 224-228
        • Pennington K.P.
        • Walsh T.
        • Harrell M.I.
        • Lee M.K.
        • Pennil C.C.
        • Rendi M.H.
        • Thornton A.
        • Norquist B.M.
        • Casadei S.
        • Nord A.S.
        • Agnew K.J.
        • Pritchard C.C.
        • Scroggins S.
        • Garcia R.L.
        • King M.C.
        • Swisher E.M.
        Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.
        Clin Cancer Res. 2014; 20: 764-775